Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor - PubMed (original) (raw)
Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor
L Hong et al. Science. 2000.
Abstract
Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease involved in the production of beta-amyloid peptide in Alzheimer's disease and is a major target for drug design. We determined the crystal structure of the protease domain of human memapsin 2 complexed to an eight-residue inhibitor at 1.9 angstrom resolution. The active site of memapsin 2 is more open and less hydrophobic than that of other human aspartic proteases. The subsite locations from S4 to S2' are well defined. A kink of the inhibitor chain at P2' and the change of chain direction of P3' and P4' may be mimicked to provide inhibitor selectivity.
Similar articles
- Subsite specificity of memapsin 2 (beta-secretase): implications for inhibitor design.
Turner RT 3rd, Koelsch G, Hong L, Castanheira P, Ermolieff J, Ghosh AK, Tang J. Turner RT 3rd, et al. Biochemistry. 2001 Aug 28;40(34):10001-6. doi: 10.1021/bi015546s. Biochemistry. 2001. PMID: 11513577 - Flap position of free memapsin 2 (beta-secretase), a model for flap opening in aspartic protease catalysis.
Hong L, Tang J. Hong L, et al. Biochemistry. 2004 Apr 27;43(16):4689-95. doi: 10.1021/bi0498252. Biochemistry. 2004. PMID: 15096037 - Memapsin 2 (beta-secretase) as a therapeutic target.
Hong L, Turner RT 3rd, Koelsch G, Ghosh AK, Tang J. Hong L, et al. Biochem Soc Trans. 2002 Aug;30(4):530-4. doi: 10.1042/bst0300530. Biochem Soc Trans. 2002. PMID: 12196130 Review. - Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase).
Ghosh AK, Bilcer G, Harwood C, Kawahama R, Shin D, Hussain KA, Hong L, Loy JA, Nguyen C, Koelsch G, Ermolieff J, Tang J. Ghosh AK, et al. J Med Chem. 2001 Aug 30;44(18):2865-8. doi: 10.1021/jm0101803. J Med Chem. 2001. PMID: 11520194 - Structural features of human memapsin 2 (beta-secretase) and their biological and pathological implications.
Hong L, He X, Huang X, Chang W, Tang J. Hong L, et al. Acta Biochim Biophys Sin (Shanghai). 2004 Dec;36(12):787-92. doi: 10.1093/abbs/36.12.787. Acta Biochim Biophys Sin (Shanghai). 2004. PMID: 15592644 Review.
Cited by
- Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors.
Ghosh AK, Pandey S, Gangarajula S, Kulkarni S, Xu X, Rao KV, Huang X, Tang J. Ghosh AK, et al. Bioorg Med Chem Lett. 2012 Sep 1;22(17):5460-5. doi: 10.1016/j.bmcl.2012.07.043. Epub 2012 Jul 20. Bioorg Med Chem Lett. 2012. PMID: 22863204 Free PMC article. - Membrane proteases in the bacterial protein secretion and quality control pathway.
Dalbey RE, Wang P, van Dijl JM. Dalbey RE, et al. Microbiol Mol Biol Rev. 2012 Jun;76(2):311-30. doi: 10.1128/MMBR.05019-11. Microbiol Mol Biol Rev. 2012. PMID: 22688815 Free PMC article. Review. - Predicting memapsin 2 (β-secretase) hydrolytic activity.
Li X, Bo H, Zhang XC, Hartsuck JA, Tang J. Li X, et al. Protein Sci. 2010 Nov;19(11):2175-85. doi: 10.1002/pro.502. Protein Sci. 2010. PMID: 20853423 Free PMC article. - Continuing strategies for inhibiting Alzheimer's gamma-secretase.
Wolfe MS, Esler WP, Das C. Wolfe MS, et al. J Mol Neurosci. 2002 Aug-Oct;19(1-2):83-7. doi: 10.1007/s12031-002-0015-5. J Mol Neurosci. 2002. PMID: 12212799 - Study of memapsin 2 (beta-secretase) and strategy of inhibitor design.
Tang J, Ghosh AK, Hong L, Koelsch G, Turner RT 3rd, Chang W. Tang J, et al. J Mol Neurosci. 2003;20(3):299-304. doi: 10.1385/JMN:20:3:299. J Mol Neurosci. 2003. PMID: 14501012 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases